Pharmaceutics

24 pages, 1884 KB

Open AccessArticle

Determining Critical Physiological and Drug Specific Parameters for Enhancing a Physiologically Based Pharmacokinetics Model for the Female Reproductive Tract

by An Le, Riyazuddin Mohammed, Junmei Zhang, Lin Wang, Guru R. Valicherla, Phillip W. Graebing, Robert Bies and Lisa C. Rohan

Pharmaceutics 2026, 18(7), 903; https://doi.org/10.3390/pharmaceutics18070903 - 22 Jul 2026

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Abstract

Background/Objectives: Given the potential for achieving high concentrations at the target site while limiting systemic exposure, delivering drugs directly to the female reproductive tract (FRT) is emerging as a promising strategy for enhancing women’s reproductive health. However, quantitative data describing matrix-specific solubility, [...] Read more.

Background/Objectives: Given the potential for achieving high concentrations at the target site while limiting systemic exposure, delivering drugs directly to the female reproductive tract (FRT) is emerging as a promising strategy for enhancing women’s reproductive health. However, quantitative data describing matrix-specific solubility, matrix-specific binding, and permeability across FRT tissues remain limited, constraining development of physiologically based pharmacokinetic (PBPK) models for intravaginal and intrauterine therapies. Methods: Our work was conducted to help fill this critical gap, evaluating four model drugs with diverse physicochemical and transporter profiles, dapivirine (DPV), levonorgestrel (LNG), MK-2048, and 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA; also known as islatravir or MK-8591) in in vitro and ex vivo human models. Plasma solubility, matrix-specific binding in plasma, cervicovaginal fluid, and FRT tissues, and bidirectional permeability across FRT tissues were quantified. Results: Our results demonstrated that the plasma solubility varied markedly across compounds, following lipophilicity trends, with DPV (34.14 ± 1.04 µg/mL) and EFdA (1808.02 ± 67.36 µg/mL) exhibiting the lowest and highest solubility, respectively. Hydrophobicity-dependent solubility enhancement by plasma proteins (~2× to >30× higher comparing to aqueous solubility in the literature) was observed for all four model drugs. Apparent binding in plasma, cervicovaginal fluid, and FRT tissues was highly correlated with the model compounds’ lipophilicity, with DPV having the most highly matrix-specific binding (97–99%) and EFdA having the least matrix-specific binding with the greatest variability (15–62%). Regional permeability differed significantly across FRT tissues: the human ectocervix, myometrium, endometrium, and fallopian tubes demonstrated distinct transport patterns consistent with epithelial architecture and the transporter-substrate status of the model compounds. Efflux transporter involvement was evident for MK-2048 and EFdA in Caco-2 models (efflux ratios 2.59 and 7.14, respectively), but was less pronounced in the 3D vaginal model and ex vivo tissues. Across all datasets, permeability and binding were strongly influenced by drug lipophilicity and ionization characteristics. Conclusions: Collectively, these findings demonstrate the interplay among solubility, matrix-specific binding, and tissue permeability in governing local drug distribution within the FRT. The experimentally derived parameters provide quantitative inputs for FRT PBPK model development, and are expected to inform design of safe and effective localized therapies for women’s reproductive health. Full article

(This article belongs to the Special Issue Advancing HIV Prevention and Treatment: Pharmacokinetics, Pharmacodynamics, Toxicokinetics, Formulation and Delivery of Antiretroviral Drugs)

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36 pages, 1940 KB

Open AccessReview

Advances in Intranasal CNS Targeting: Integrating Formulations, Devices, Computational Fluid Dynamics, and 3D Printing

by Lena Shaghlil, Yousef Al-Ebini, Mahmoud J. Al Shawabkeh, Fatmawati Adam, Kuldeep K. Saxena, Anas Alshishani and Wan Sharuzi Wan Harun

Pharmaceutics 2026, 18(7), 902; https://doi.org/10.3390/pharmaceutics18070902 - 22 Jul 2026

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Abstract

Nose-to-brain (N2B) delivery is a practical, non-invasive strategy for CNS targeting that can increase brain exposure while limiting systemic exposure. This review integrates three milestones in N2B delivery, formulations, devices, and quantitative evaluation strategies, to define design rules for effective olfactory/trigeminal deposition and [...] Read more.

Nose-to-brain (N2B) delivery is a practical, non-invasive strategy for CNS targeting that can increase brain exposure while limiting systemic exposure. This review integrates three milestones in N2B delivery, formulations, devices, and quantitative evaluation strategies, to define design rules for effective olfactory/trigeminal deposition and enhance translational relevance. Formulations emphasize mucoadhesive systems, nanoparticle carriers (polymeric, lipid-based, and hybrid), nano-emulsions, and stimuli-responsive “smart” gels that prolong nasal residence. Regarding device advancements, the review covers conventional nasal sprays optimized for plume geometry and droplet size. Furthermore, it examines breath-actuated metered sprays, which promote soft palate closure to route aerosols to superior regions, and vibrating mesh nebulizers capable of low-velocity mists for improved upper cavity deposition. Quantitative evaluation is discussed, including 3D-printed, anatomy-accurate nasal casts, high-speed spray diagnostics, and computational fluid dynamics (CFD). This review further links formulation and device parameters to regional deposition. Available clinical and animal data illustrate the feasibility of these approaches, safety considerations, and user-technique dependencies, while highlighting the need for standardized, anatomy-aware testing protocols. Together, these developments suggest that co-designed formulation device platforms, validated by cast/CFD metrics and supported by clinical imaging or pharmacokinetic data, can support N2B product development toward consistent, patient-relevant outcomes. Full article

(This article belongs to the Topic Challenges and Opportunities in Drug Delivery Research, 2nd Edition)

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14 pages, 9118 KB

Open AccessArticle

Cell Membrane-Modified Lipid Nanoparticle Enhanced Glioblastoma Immunotherapy via Metabolism Reprogramming and Pyroptosis Induction

by Pengxuan Zhao, Yu Tian, Weigang Yuan, Yang Bai, Yue Zhu, Liunuosi Wang, Ruoyi Wu, Fuchou Han and Ting Fan

Pharmaceutics 2026, 18(7), 901; https://doi.org/10.3390/pharmaceutics18070901 - 22 Jul 2026

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Abstract

Background: Glioblastoma (GBM) has emerged as a model of resistance to immunotherapy because of the immunosuppressive tumor microenvironment (TME), which is closely associated with tryptophan metabolism. Inhibiting the expression of indoleamine 2,3-dioxygenase-1 (IDO1, a key enzyme in tryptophan metabolism) is a promising strategy [...] Read more.

Background: Glioblastoma (GBM) has emerged as a model of resistance to immunotherapy because of the immunosuppressive tumor microenvironment (TME), which is closely associated with tryptophan metabolism. Inhibiting the expression of indoleamine 2,3-dioxygenase-1 (IDO1, a key enzyme in tryptophan metabolism) is a promising strategy for improving the immunosuppressive TME. Meanwhile, Gasdermin B (GSDMB)-mediated pyroptosis is a newly identified mechanism for activating the immune response. Methods: We prepared a GBM cell membrane (CM)-modified lipid nanoparticle (CMLNP) to deliver CRISPR/Cas9 components and mRNA encoding the N-terminal domain of GSDMB (GSDMB^NT mRNA). Results: The CM modification endowed the LNP with a tumor homing/homotypic targeting effect. Then, CRISPR/Cas9 components realized the knockdown of the IDO1 gene, thus remodeling the TME. GSDMB^NT mRNA triggers pyroptosis, thus eliciting an immune response. Conclusions: This system generated potent antitumor immunity and offered a novel strategy for GBM immunotherapy. Full article

(This article belongs to the Section Gene and Cell Therapy)

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19 pages, 3582 KB

Open AccessArticle

Aqueous Artemisia herba-alba Asso Preparation as a Botanical Adjunct to Dapagliflozin: Enhanced Glycemic Control in Streptozotocin-Induced Diabetic Rats

by Mohammad M. Hailat, Mustafa M. Al-Karkhi, Nisreen T. Al-Qaisi, Marwan Shalash, Wael Abu Dayyih, Wafa Hourani, Mohammad Abu Assab, Ahmed Bassam Farhan, Abdul Rahman Abu Dayyih, Shorouq B. Talalah and Afnan B. Talalah

Pharmaceutics 2026, 18(7), 900; https://doi.org/10.3390/pharmaceutics18070900 - 22 Jul 2026

Viewed by 392

Abstract

Background/Objectives: optimization of the therapeutic efficacy of antidiabetic agents is still a great challenge in the management of type 2 diabetes mellitus (T2DM), and attention is becoming more and more focused on the use of adjunctive agents that help target the drug [...] Read more.

Background/Objectives: optimization of the therapeutic efficacy of antidiabetic agents is still a great challenge in the management of type 2 diabetes mellitus (T2DM), and attention is becoming more and more focused on the use of adjunctive agents that help target the drug action beyond the classic glycemic target. This study examined the effect of co-administration of an Artemisia herba-alba Asso (Asteraceae) aqueous extract on the glucose-lowering effect of dapagliflozin, a sodium–glucose cotransporter-2 (SGLT2) inhibitor. Methods: qualitative phytochemical screening and total phenolic and total flavonoid content were used to characterize the aqueous preparation. Male Wistar albino rats were divided into eight groups (10 rats each): four healthy and four diabetic rats induced with streptozotocin (STZ). Vehicle control, oral administration of an aqueous A. herba-alba preparation (0.39 g/kg twice daily), dapagliflozin (0.143 mg/kg/day), or a combination of both was given for 30 days. At baseline and days 7, 14, 21, and 30, glycated hemoglobin (HbA1c) was measured by nephelometry. Parallel fasting blood glucose (FBG) was monitored. Results: the diabetic animals treated with the combination regimen showed the greatest and most sustained decrease in HbA1c (from 4.42 ± 0.40% at baseline to 3.44 ± 0.17% at day 30; p < 0.001) and the greatest decrease in FBG (from 186.0 to 122.2 mg/dL). A. herba-alba monotherapy had little effect on HbA1c and had minimal effect on FBG (214.9 to 217.6 mg/dL); dapagliflozin monotherapy had a modest effect on HbA1c. The untreated diabetic controls (n = 10) showed a progressive increase in HbA1c from 4.45 ± 0.60% at 72 h post-induction to 11.90 ± 0.99% by day 30 (p < 0.001), consistent with delayed hemoglobin glycation relative to the rise in blood glucose. The repeated-measures ANOVA showed a highly significant interaction between time and treatment (p < 0.001). Conclusions: this study showed that the phytochemically defined aqueous A. herba-alba preparation is a beneficial adjunct to SGLT2 inhibitor therapy, an effect not observed with either treatment alone. Full article

(This article belongs to the Special Issue Advances in Delivery Systems for Antidiabetic Drugs and Beyond Glycaemic Control)

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29 pages, 4031 KB

Open AccessArticle

Enhancing Oral Bioavailability of Poorly Water-Soluble Natural Products via Lipid–Drug Conjugates

by Xiaoli Zou, Bin Zhang, Lianghe Mei, Sifei Han and Kaixian Chen

Pharmaceutics 2026, 18(7), 899; https://doi.org/10.3390/pharmaceutics18070899 - 22 Jul 2026

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Abstract

Background: The therapeutic potential of many natural products, including curcumin (CUR), betulinic acid (BA), and oleanolic acid (OA), is limited by poor oral exposure caused by low aqueous solubility, metabolic instability, and/or first-pass metabolism. Lipid–drug conjugate (LDC) strategies that mimic endogenous dietary lipid [...] Read more.

Background: The therapeutic potential of many natural products, including curcumin (CUR), betulinic acid (BA), and oleanolic acid (OA), is limited by poor oral exposure caused by low aqueous solubility, metabolic instability, and/or first-pass metabolism. Lipid–drug conjugate (LDC) strategies that mimic endogenous dietary lipid processing may provide a useful approach for improving oral absorption and lymphatic transport. Methods: A 1,3-diolein-based lipidic promoiety (IN-4) was synthesized and conjugated to curcumin, betulinic acid, and oleanolic acid to generate three representative LDCs: CUR-PRO, BA-PRO, and OA-PRO. Their oral pharmacokinetic behavior was evaluated in rats. For CUR-PRO, matched-vehicle comparisons across three oral vehicles were performed, together with mesenteric lymph duct cannulation and in vitro stability/conversion studies in simulated gastrointestinal media, rat liver microsomes, and rat plasma. Results: All three prodrugs were successfully synthesized and showed improved systemic exposure to the corresponding parent-drug-related analytes under the tested conditions. For CUR-PRO, dose-normalized AUC_0-last of released curcumin was markedly higher than direct curcumin administration across all three vehicles (increases of 15.0-, 70.9-, and 54.3-fold), and intact CUR-PRO was also detected in plasma. Mesenteric lymph sampling showed that CUR-PRO dosing, but not free-curcumin dosing, generated detectable curcumin-related signals under the present analytical conditions. In vitro, no free curcumin was detected during CUR-PRO incubation in enzyme-free simulated gastrointestinal media; CUR-PRO underwent rapid depletion in pancreatic-lipase-supplemented medium, showed greater microsomal stability than curcumin, and displayed plasma conversion that was markedly accelerated by exogenous LPL. BA-PRO and OA-PRO also increased systemic exposure of their released parent drugs, with 16.0- and 38.4-fold dose-normalized AUC_0-last increases, respectively. Conclusions: These findings provide proof-of-concept evidence that 1,3-diolein-based lipidation can improve the oral exposure of selected poorly water-soluble natural products. The lymphatic transport data provide qualitative evidence supporting lymphatic access of CUR-PRO, although the quantitative contribution of this pathway to the overall exposure increase remains to be established. Full article

(This article belongs to the Special Issue Novel Strategies for Enhancing Oral Bioavailability)

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16 pages, 7093 KB

Open AccessArticle

Dorsal Root Ganglion-Targeted DNA Origami Delivery of IL1RN for Skeletal Growth and Repair

by Yumiao Jiang, Xinyi Gu, Zenglin Yin, Shen Wang, Jin Deng, Shuhang Guo and Xiaofeng Yin

Pharmaceutics 2026, 18(7), 898; https://doi.org/10.3390/pharmaceutics18070898 - 22 Jul 2026

Viewed by 420

Abstract

Background/Objectives: Sensory nerves, as essential peripheral nerves, innervate bone and release various neuroactive substances—including neurotransmitters, neuropeptides, and neurocrine factors—that participate in bone growth, remodeling, and metabolism. Interleukin-1 receptor antagonist (IL1RN), an endogenous anti-inflammatory mediator, is a key regulatory molecule in the pathogenesis of [...] Read more.

Background/Objectives: Sensory nerves, as essential peripheral nerves, innervate bone and release various neuroactive substances—including neurotransmitters, neuropeptides, and neurocrine factors—that participate in bone growth, remodeling, and metabolism. Interleukin-1 receptor antagonist (IL1RN), an endogenous anti-inflammatory mediator, is a key regulatory molecule in the pathogenesis of inflammatory diseases such as osteoarthritis and rheumatoid arthritis. However, its role as a sensory neurocrine factor in the regulation of bone tissue has rarely been investigated. This study aimed to explore the regulatory effects of sensory nerve–derived IL1RN on bone tissue. Methods: A dorsal root ganglion (DRG)-targeted delivery system was developed using DNA origami technology to load IL1RN protein or IL1RN-targeting siRNA and was functionalized with a DRG-homing peptide. Bone defect and age-related bone loss models were established in C57BL/6 mice to preliminarily investigate the regulatory role of IL1RN secreted from sensory nerve endings in bone tissue. Results: IL1RN suppressed bone resorption and promoted new bone formation at defect sites. In the age-related bone loss model, IL1RN preserved the integrity of the growth plate. These findings indicate that sensory nerve–derived IL1RN may participate in the regulation of bone repair and skeletal homeostasis. Conclusions: IL1RN may serve as a potential therapeutic target for DRG-mediated regulation of bone repair. These findings suggest that DRG-targeted modulation of IL1RN may represent a potential approach for investigating and regulating sensory nerve–associated bone repair. Full article

(This article belongs to the Section Drug Targeting and Design)

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28 pages, 12012 KB

Open AccessArticle

Curcumin-Loaded Microemulsion Gel: An Optimized and Rheologically Acceptable Formulation with Conducive Dermatokinetics for Topical Breast Cancer Therapy

by Md. Abul Barkat, Shakilur Rahman, Harshita Barkat, Abdulkareem A. Alanezi, Nader I. Namazi, Afaf F. Almuqati, Abrar Turki, Zahraa Alali, Mahesh Kumar Sharma and Kaisar Raza

Pharmaceutics 2026, 18(7), 897; https://doi.org/10.3390/pharmaceutics18070897 - 21 Jul 2026

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Abstract

Background/Objectives: Breast cancer remains one of the most prevalent malignancies worldwide, highlighting the need for safer and more effective therapeutic strategies. Curcumin has shown considerable anticancer potential; however, its clinical application is limited by poor aqueous solubility and low skin permeability. Methods [...] Read more.

Background/Objectives: Breast cancer remains one of the most prevalent malignancies worldwide, highlighting the need for safer and more effective therapeutic strategies. Curcumin has shown considerable anticancer potential; however, its clinical application is limited by poor aqueous solubility and low skin permeability. Methods: Therefore, a curcumin-loaded microemulsion (CUR-ME) was developed and optimized using a Box–Behnken design, followed by incorporation into a Carbopol 934 gel for topical breast cancer therapy. Results: The optimized formulation exhibited a particle size of 177.4 nm, a polydispersity index of 0.1309, and a zeta potential of −4.45 mV, indicating favorable physicochemical characteristics. CUR-ME demonstrated superior dose-dependent cytotoxicity against MCF-7 breast cancer cells, with a lower IC₅₀ 8.89 µg/mL than free curcumin IC₅₀ 9.83 µg/mL. Furthermore, Hoechst 33342 staining and the DCFDA assay confirmed enhanced apoptosis and intracellular reactive oxygen species generation in CUR-ME-treated cells, indicating improved cellular uptake and anticancer activity. Rheological and texture profile analyses demonstrated suitable viscosity, firmness, and spreadability for topical application. In vitro drug release revealed sustained release from the CUR-ME gel, achieved through the polymeric gel matrix, which increased viscosity, entrapped microemulsion droplets, and acted as a diffusion barrier to prolong drug retention and release. Confocal laser scanning microscopy further confirmed enhanced skin penetration of CUR-ME. Conclusions: Collectively, these findings demonstrate that the developed CUR-ME gel is a promising topical drug delivery system with sustained release, improved skin retention, and enhanced therapeutic potential for breast cancer management. Full article

(This article belongs to the Special Issue Nanocomposite Hydrogels and Their Application in Drug Delivery and Tissue Engineering)

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18 pages, 9664 KB

Open AccessArticle

Structure–Function Relationships in Polysaccharide–Iron Complexes: Molecular Characterization, Acid-Stress Release Stability, and Gastrointestinal Tolerability

by Xiangqiu Qi, Hongwei Zhu, Xin Yan, Xi Kang, Dandan Xiao and Xianyi Sha

Pharmaceutics 2026, 18(7), 896; https://doi.org/10.3390/pharmaceutics18070896 - 21 Jul 2026

Viewed by 294

Abstract

Background: Polysaccharide–iron complexes (PICs) are widely used oral iron supplements, but their gastrointestinal tolerability varies and remains incompletely understood. As typical non-biological complex drugs (NBCDs), PICs exhibit structural heterogeneity, and their functional performance may be linked to higher-order structural attributes. Methods: [...] Read more.

Background: Polysaccharide–iron complexes (PICs) are widely used oral iron supplements, but their gastrointestinal tolerability varies and remains incompletely understood. As typical non-biological complex drugs (NBCDs), PICs exhibit structural heterogeneity, and their functional performance may be linked to higher-order structural attributes. Methods: In this study, two commercial PIC preparations (test samples A and B) were comparatively investigated to explore their structure–function relationship using a multi-dimensional approach. Structural properties were characterized by gel permeation chromatography (GPC), mass spectrometry (MS), Fourier-transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) spectroscopy, along with monosaccharide composition analysis. Functional behaviors and physiological relevance were further evaluated through in vitro acid-stress release studies and in vivo rat gastrointestinal tolerability assessments. Results: The results revealed that test sample A exhibited a glucose-only detectable monosaccharide profile but a higher and broader apparent molecular-weight distribution, indicating monosaccharide compositional uniformity together with macromolecular heterogeneity. In contrast, test sample B showed detectable glucose and mannose, a lower and narrower apparent molecular-weight distribution, higher measured free iron, and greater iron release under the tested acidic conditions. An exploratory 7-day rat gastrointestinal tolerability study (n = 4 per group) indicated that these distinct profiles may impact mucosal tolerability. Structurally stable test sample A allowed intestinal iron accumulation while maintaining mucosal integrity. Conversely, the rapid dissociation of test sample B induced observable mucosal injury, despite lower local iron retention. Conclusions: These findings suggest that the gastrointestinal tolerability of PICs may be associated with their structural attributes and release behavior, rather than total iron content alone. Overall, this exploratory study highlights a potential relationship between multi-dimensional PIC structure and functional performance, emphasizing the need for broader, structure-informed frameworks in the quality evaluation of complex iron therapies. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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20 pages, 9657 KB

Open AccessArticle

Isolation and Characterization of a Novel Marine Peptide, WPN-15, from Walleye Pollock (Gadus chalcogrammus) Tail By-Products and Its Therapeutic Effects Against Atopic Dermatitis

by Sung-Gyu Lee, Jin-Woo Hwang and Hyun Kang

Pharmaceutics 2026, 18(7), 895; https://doi.org/10.3390/pharmaceutics18070895 - 21 Jul 2026

Viewed by 405

Abstract

Background/Objectives: Atopic dermatitis (AD) is a multifactorial inflammatory skin disorder in which epidermal barrier disruption and dysregulated immune responses drive persistent cutaneous inflammation. Owing to their broad spectrum of biological activities, marine-derived peptides have attracted increasing attention as potential therapeutic agents capable [...] Read more.

Background/Objectives: Atopic dermatitis (AD) is a multifactorial inflammatory skin disorder in which epidermal barrier disruption and dysregulated immune responses drive persistent cutaneous inflammation. Owing to their broad spectrum of biological activities, marine-derived peptides have attracted increasing attention as potential therapeutic agents capable of modulating inflammatory and immune pathways. Methods: In this study, a novel peptide, WPN-15 (NGAIADQQPQRPNIV), was isolated from enzymatic hydrolysates of walleye pollock (Gadus chalcogrammus) tail by-products using an activity-guided purification process consisting of dialysis, fast protein liquid chromatography-gel permeation chromatography (FPLC-GPC), reverse-phase high-performance liquid chromatography (RP-HPLC), and electrospray ionization mass spectrometry (ESI-MS). The anti-inflammatory activity of WPN-15 was first examined in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, and subsequently validated in a 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis model using six-week-old male BALB/c mice. Results: WPN-15 significantly inhibited nitric oxide production in LPS-stimulated macrophages without causing cytotoxic effects. Topical administration of WPN-15 markedly alleviated DNCB-induced AD-like kin lesions, significantly reduced dermatitis severity scores, and decreased serum interleukin (IL)-6 levels. Histological evaluation further demonstrated that WPN-15 attenuated epidermal hyperplasia, dermal thickening, and mast cell infiltration. Furthermore, WPN-15 significantly downregulated the mRNA expression of IL-1β and IL-6 and inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation in skin tissues, indicating that its protective effects are mediated, at least in part, through the suppression of the IL-6/STAT3 signaling pathway. Conclusions: WPN-15 effectively attenuated inflammatory responses and pathological features associated with experimental AD. These findings demonstrate that walleye pollock tail by-products represent a valuable and sustainable source of bioactive peptides and support the potential application of WPN-15 as a marine-derived therapeutic candidate for the management of AD. Full article

(This article belongs to the Section Drug Targeting and Design)

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21 pages, 15918 KB

Open AccessArticle

Development of Nanosystems Delivering with Eco-Friendly Antibacterial Agents Composed of Zingiber officinale/Alpinia galanga and Gold, as Sustainable Antibiotics

by Rosa M. Giráldez-Pérez, Elia M. Grueso, Alfonso Carbonero, Antonio Carpintero-López and Rafael Prado-Gotor

Pharmaceutics 2026, 18(7), 894; https://doi.org/10.3390/pharmaceutics18070894 - 21 Jul 2026

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Abstract

Background/Objectives: Green antibacterial synthesis is a natural alternative to chemical methods, aligning with the Sustainable Development Goals by being beneficial to the environment and contributing to new therapies to combat antibiotic resistance. In this research, a simple method was developed for producing nanosystems [...] Read more.

Background/Objectives: Green antibacterial synthesis is a natural alternative to chemical methods, aligning with the Sustainable Development Goals by being beneficial to the environment and contributing to new therapies to combat antibiotic resistance. In this research, a simple method was developed for producing nanosystems with natural extracts of Ginger (Zingiber officinale) or Galangal (Alpinia galanga) with gold. Then, their antibacterial efficacy was evaluated and compared against strains of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Methods: After optimizing the systems, the core size of the nanosystems was determined using transmission electron microscopy (TEM), and the presence of gold was confirmed with EDS. Stability control was measured using spectrometry, and the systems were characterized by measuring zeta potential and dynamic light scattering (DLS). Finally, to verify the antibacterial effect, minimum inhibitory concentration (MIC) assays were performed. Results: The analysis of the MIC experiments confirmed that the Galangal nanosystem (Au@Galangal showed better results against both bacteria. In the case of the Ginger nanosystem (Au@Ginger), the most evident results were against E. coli. Internalization studies demonstrated the antibacterial efficacy of all the nanosystems analyzed. Conclusions: The results suggest that nanosystems obtained entirely by green methods have great potential as alternative antimicrobial agents, especially against resistant strains, representing a major advance in the development of sustainable bactericidal nanosystems. Full article

(This article belongs to the Special Issue Drug Nanocarriers for Pharmaceutical Applications, 2nd Edition)

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20 pages, 6190 KB

Open AccessArticle

Engineering Poly(Lactic-co-Glycolic Acid) (PLGA)-Based Microspheres for Controlled Corticosteroid Delivery in Intra-Articular Cartilage

by Pamela Rose V. Samonte and Noelle K. Comolli

Pharmaceutics 2026, 18(7), 893; https://doi.org/10.3390/pharmaceutics18070893 - 21 Jul 2026

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Abstract

Background: Osteoarthritis (OA), affecting approximately 240 million people worldwide, currently lacks targeted, long-acting therapeutic options. This study investigates how physicochemical properties (i.e., size, surface charge, polydispersity) influence poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) diffusion into articular cartilage for enhanced corticosteroid delivery. Methods: [...] Read more.

Background: Osteoarthritis (OA), affecting approximately 240 million people worldwide, currently lacks targeted, long-acting therapeutic options. This study investigates how physicochemical properties (i.e., size, surface charge, polydispersity) influence poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) diffusion into articular cartilage for enhanced corticosteroid delivery. Methods: PLGA MSs were synthesized via oil/water emulsions to create a variety of sizes and surface charges. MSs were loaded with corticosteroid (H-17-B) and release kinetics were studied in vitro and analyzed via HPLC. Diffusion of the MSs was investigated via a bovine explant model. Results: Unmodified PLGA MSs (approximately 0.58–0.98 µm) were synthesized via single-stage oil/water emulsion with varying poly(vinyl alcohol) concentrations and sonication intensities. All formulations exhibited near-neutral surface charges (−0.27 to 4.28 mV). Smaller particles achieved greater cartilage penetration, with bi-exponential diffusion models (R² = 0.706–0.999) outperforming classical Fickian approaches. However, multi-timepoint validation demonstrated fundamentally non-diffusive transport, likely governed by steric exclusion from the dense collagen network (0.05–0.06 µm pore size). Surface functionalization with avidin/palmitic acid or polyethylene glycol (PEG)/biotin yielded microspheres with controlled properties (0.36–0.97 µm; PDI: 0.10–0.32). In vitro release studies with hydrocortisone-17-butyrate (H-17-B; encapsulation efficiency of 79.8% ± 4.8%) demonstrated biphasic kinetics best fit by bi-exponential models (R² > 0.95). Unmodified microspheres exhibited 7.1% cumulative release by Day 14. High-performance liquid chromatography revealed that H-17-B undergoes ester hydrolysis to hydrocortisone during release, with surface modifications significantly affecting drug stability. Specifically, PEGylated microspheres maintained 96% of the drug in H-17-B form at Day 14 compared to only 37% for unmodified particles. Release was governed by PLGA degradation with concentration-independent kinetics, enabling predictable dose scalability. Conclusions: This work establishes that the behavior of PLGA microspheres in cartilage is controlled by size, charge, and surface functionalization. Surface modifications overcome physical barriers while stabilizing the encapsulated corticosteroid against premature hydrolysis, providing a framework for designing intra-articular drug delivery systems for osteoarthritis treatment. Full article

(This article belongs to the Special Issue PLGA Micro/Nanoparticles in Drug Delivery)

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3 pages, 128 KB

Open AccessEditorial

Nanotechnology in Cancer Prevention, Diagnosis, and Treatment

by Hyun-Ouk Kim

Pharmaceutics 2026, 18(7), 892; https://doi.org/10.3390/pharmaceutics18070892 - 21 Jul 2026

Viewed by 272

Abstract

Nanotechnology has evolved from a promising idea to a working element in how we detect and treat disease [...] Full article

(This article belongs to the Special Issue Nanotechnology Applied in Prevention, Diagnosis and Treatment of Cancer)

3 pages, 128 KB

Open AccessEditorial

Recent Advances in Nanotechnology Therapeutics

by Hyun-Ouk Kim

Pharmaceutics 2026, 18(7), 891; https://doi.org/10.3390/pharmaceutics18070891 - 20 Jul 2026

Viewed by 1227

Abstract

Nanotechnology has moved from a promising idea to a working part of how we treat disease [...] Full article

(This article belongs to the Special Issue Recent Advances in Nanotechnology Therapeutics)

3 pages, 137 KB

Open AccessEditorial

Cell-Mediated Drug Delivery: From Carriers to Therapeutics

by Lisa Gherardini and Monia Taranta

Pharmaceutics 2026, 18(7), 890; https://doi.org/10.3390/pharmaceutics18070890 - 20 Jul 2026

Viewed by 320

Abstract

Nanomedicine has profoundly transformed the delivery of therapeutic agents by improving drug pharmacokinetics, protecting labile cargos, and expanding the therapeutic potential of a wide range of molecules [...] Full article

(This article belongs to the Special Issue Cell-Mediated Delivery Systems)

14 pages, 7280 KB

Open AccessArticle

Optimization of Gravity Infusion Protocols for ¹⁷⁷Lu-DOTATATE Administration in Peptide Receptor Radionuclide Therapy

by Salvatore Grasso, Antonio Varallo, Valeria Gaudieri, Michele Klain, Roberta Pastore, Stefania Arena, Caterina Oliviero, Mauro Buono, Daniele Manzi, Regina Schiano, Carmela Nappi, Pasquale Totaro, Rosario Raffaele Bonifacio, Alberto Cuocolo and Stefania Clemente

Pharmaceutics 2026, 18(7), 889; https://doi.org/10.3390/pharmaceutics18070889 - 20 Jul 2026

Viewed by 427

Abstract

Background: Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE has become a cornerstone in the management of neuroendocrine tumors (NETs). However, the efficiency of this targeted therapy is highly dependent on the radiopharmaceutical drug delivery system and its infusion kinetics, which influence systemic [...] Read more.

Background: Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE has become a cornerstone in the management of neuroendocrine tumors (NETs). However, the efficiency of this targeted therapy is highly dependent on the radiopharmaceutical drug delivery system and its infusion kinetics, which influence systemic biodistribution and therapeutic efficacy. This study evaluates various gravity-based infusion fluid dynamics to optimize the drug delivery profile, ensuring standardized delivery while minimizing residual activity. Methods: A retrospective analysis of 127 administrations of ¹⁷⁷Lu-DOTATATE (7.4 GBq per cycle) was conducted across 35 patients with NETs to assess vial dilution kinetics. Four distinct infusion rate (IR) strategies were compared to evaluate mass balance and delivery efficiency: constant infusion rate (1-IR); a single rate increase at 10 min (2-IR); two rate increases at 10 and 30 min (3-IR); and three rate increases at 10, 30, and 40 min (4-IR). Results: Stepwise increases in the IR significantly accelerated the vial clearance kinetics and reduced radiopharmaceutical stagnation within the infusion lines. Successful delivery of the target dose (98% of the pre-infusion activity measured in each specific vial) was achieved in 56% of cases with the 1-IR protocol (9 injections) and increased to 87% with 2-IR (45 injections), 97% with 3-IR (60 injections), and 100% with 4-IR (13 injections). Conclusions: Modulating fluid dynamics through stepwise IR protocols significantly enhances radiopharmaceutical delivery efficiency. The 3-IR protocol offers a favorable balance between procedural efficiency and clinical safety. Full article

(This article belongs to the Special Issue Drug Delivery Strategies and Novel Approaches for Cancer Treatment)

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30 pages, 3955 KB

Open AccessArticle

Electrospun Polymeric Nanofibers Incorporating Brazilian Red Propolis Extract for Wound Dressing Applications

by Maria Sirlene Morais, Paulo Augusto Marques Chagas, Gustavo Cardoso da Mata, Gabriela Rodrigues Silva, Elaine Cristina Pereira De Martinis, Guilherme Henrique Alves Pinto, Gabriela Fávero Galvão, Monica Lopes Aguiar and Wanderley Pereira Oliveira

Pharmaceutics 2026, 18(7), 888; https://doi.org/10.3390/pharmaceutics18070888 - 20 Jul 2026

Viewed by 484

Abstract

Background/Objectives: Chronic wounds remain difficult to manage because persistent inflammation, microbial colonization, and excess exudate require dressings that combine structural integrity, bioactivity, antimicrobial performance, and cytocompatibility. This study aimed to develop electrospun nanofibrous mats based on gelatin, poly(vinyl alcohol) (PVA), and poly(ε-caprolactone) [...] Read more.

Background/Objectives: Chronic wounds remain difficult to manage because persistent inflammation, microbial colonization, and excess exudate require dressings that combine structural integrity, bioactivity, antimicrobial performance, and cytocompatibility. This study aimed to develop electrospun nanofibrous mats based on gelatin, poly(vinyl alcohol) (PVA), and poly(ε-caprolactone) (PCL), with and without Brazilian red propolis extract (BRPE), and to evaluate how extract incorporation affects solution properties, fiber morphology, fluid interaction, antimicrobial activity, and cytocompatibility. Methods: BRPE was characterized in terms of solid content, total phenolic content, antioxidant activity, and HPLC-DAD marker profile. Polymeric solutions were evaluated for electrical conductivity and rheological behavior and then processed by electrospinning under fixed conditions. The resulting mats were characterized by scanning electron microscopy, surface porosity, FTIR, and HPLC-DAD. Their performance was further assessed by swelling-associated degradation in simulated wound fluids, agar diffusion antimicrobial assays, and MTT cytocompatibility assays using HaCaT cells. Results: BRPE showed a solid content of 3.88%, a total phenolic content of 8.79 ± 0.21 mg pyrogallol equivalents g⁻¹ extract, and an antioxidant activity of 75.32 ± 9.80 mg Trolox equivalents g⁻¹ extract. HPLC-DAD confirmed preservation of the BRPE chromatographic fingerprint after electrospinning, with high retention of marker peaks associated with liquiritigenin and a formononetin-related signal. Solution conductivity varied with polymer composition and BRPE incorporation; for example, the PVA:gelatin:PCL formulation A4/A4.1 at 70:20:10 decreased from 919.6 to 539.6 µS cm⁻¹ after BRPE loading. Electrospinning produced continuous, defect-free fibers with mean diameters ranging from 94 to 224 nm and surface porosity between 9.8 and 10.6%. Most hydrophilic systems showed rapid fluid interaction but limited wet-state structural stability; among the quantified formulations, A5 showed the lowest mass loss, indicating better structural preservation under simulated wound conditions. BRPE-loaded mats showed microorganism-dependent antimicrobial activity, with the strongest inhibition against Staphylococcus epidermidis and Klebsiella pneumoniae and no activity against Pseudomonas aeruginosa. Free BRPE showed marked cytotoxicity, whereas selected electrospun formulations, especially A1.1 and A3.1, improved HaCaT cell viability. Conclusions: Electrospinning was an effective strategy for incorporating BRPE into polymeric nanofibers and modulating the physicochemical and biological performance of the resulting mats. These findings support the potential of these materials as multifunctional wound-dressing platforms, although further optimization is needed to improve wet-state structural stability, mechanical performance, and bioactive release. Full article

(This article belongs to the Special Issue Application of Electrospinning Technology in Pharmaceutical Engineering)

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35 pages, 11470 KB

Open AccessReview

Mapping Scientific Landscapes and Therapeutic Innovations of Targeted Protein Degradation: A Scientometric Review

by Chong Li, Xiangxiu Wang, Anqi He, Tianjie Bao, Weihua Zhuang, Chengqi He and Yonghong Yang

Pharmaceutics 2026, 18(7), 887; https://doi.org/10.3390/pharmaceutics18070887 - 20 Jul 2026

Viewed by 742

Abstract

Targeted Protein Degradation (TPD) has emerged as a transformative paradigm in drug discovery, offering a robust strategy to address “undruggable” targets. This study presents the first 25-year longitudinal scientometric analysis (2001–2025) of the TPD field, integrating data from 2750 publications across the Web [...] Read more.

Targeted Protein Degradation (TPD) has emerged as a transformative paradigm in drug discovery, offering a robust strategy to address “undruggable” targets. This study presents the first 25-year longitudinal scientometric analysis (2001–2025) of the TPD field, integrating data from 2750 publications across the Web of Science Core Collection, Scopus, and PubMed to map the global research landscape and therapeutic innovations. The results indicate that TPD research entered an explosive growth phase post-2016. China leads in publication volume (1247 papers), while the USA maintains dominance in citation impact (H-index = 80) and foundational leadership. The Chinese Academy of Sciences and Harvard University were identified as core institutions, with Craig M. Crews confirmed as a pivotal scholar. Thematic analysis reveals a systematic evolution from foundational ubiquitin-proteasome mechanisms to the clinical translation of advanced modalities, including Proteolysis-Targeting Chimeras (PROTACs), molecular glues, and non-ubiquitin-dependent platforms like LYTACs and AUTACs. Clinical viability is evidenced by the FDA approval of the agent ARV-471 for oncology. Despite this progress, critical challenges remain regarding E3 ligase expansion, molecular design optimization, and off-target toxicity. This review provides a data-driven roadmap for future TPD development, bridging the gap between academic output and real-world translational science to guide researchers, clinicians, and industry partners in navigating this dynamic therapeutic frontier. Full article

(This article belongs to the Special Issue Recent Advances in Inhibitors for Targeted Therapies)

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18 pages, 10720 KB

Open AccessArticle

TPGS Analog-Mediated Intracellular ROS-Amplifying Strategy Potentiates the In Vitro Anticancer Activity of a Dual-Thioketal-Linked Polymeric Drug Conjugate in A549 Lung Cancer Cells

by Hyun-Chul Kim, Kyeong-Min Lee, Yeo Jin Hwang, Jonghun Lee and Hwa Seung Han

Pharmaceutics 2026, 18(7), 886; https://doi.org/10.3390/pharmaceutics18070886 - 20 Jul 2026

Viewed by 414

Abstract

Background/Objectives: Reactive oxygen species (ROS)-responsive polymeric drug conjugates (PDCs) can enable oxidative stress-triggered drug release, but their activation may be limited by heterogeneous or insufficient intracellular ROS. Herein, we synthesized a dual-thioketal-linked PDC bearing two ROS-cleavable thioketal (TK) units in series and [...] Read more.

Background/Objectives: Reactive oxygen species (ROS)-responsive polymeric drug conjugates (PDCs) can enable oxidative stress-triggered drug release, but their activation may be limited by heterogeneous or insufficient intracellular ROS. Herein, we synthesized a dual-thioketal-linked PDC bearing two ROS-cleavable thioketal (TK) units in series and combined it with D-α-Tocopheryl polyethylene glycol succinate analog (TPGSa) as a soluble ROS-modulating co-treatment. Methods: PDC was synthesized through stepwise construction of the TK linker and subsequent carbonate coupling with camptothecin (CPT). TPGSa was prepared by esterifying mPEG with tocopheryl succinate. PDC nanoassembly formation, colloidal stability, peroxide-induced structural changes, thiol generation, and CPT release behaviors were evaluated under oxidative conditions. Cytotoxicity was examined in A549 and BEAS-2B cells with intracellular ROS- and CPT-associated fluorescence. Results: PDC formed spherical nanoassemblies with a hydrodynamic diameter of 98.6 ± 2.6 nm and a zeta potential of −13.3 ± 1.2 mV. The PDC remained colloidally dispersed in 10% FBS-containing PBS and after lyophilized storage. Peroxide exposure produced concentration-dependent thiol generation, molecular size change, and CPT release. The PDC + TPGSa reduced A549 viability more than PDC alone, produced the most pronounced dead-cell staining, and yielded the highest intracellular ROS and CPT fluorescence signals. In contrast, BEAS-2B viability remained substantially higher under matched conditions. Conclusions: These findings support an A549-focused in vitro proof of concept in which TPGSa-associated redox perturbation is paired with a dual TK PDC to enhance CPT-associated cytotoxicity. Full article

(This article belongs to the Special Issue ROS-Mediated Nano Drug Delivery for Antitumor Therapy)

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18 pages, 6279 KB

Open AccessArticle

Feasibility Study of Nose-to-Brain Delivery of Galantamine for Alzheimer’s Disease: Enhancing Olfactory-Region Deposition to Improve Therapeutic Efficacy

by Chuangxin Chen, Chunying Leung, Zizhao Zhai, Guanlin Wang, Rui Yang, Qiuyi Hu, Xiao Yue, Zhongxuan Yao, Ziyu Zhao and Xuejuan Zhang

Pharmaceutics 2026, 18(7), 885; https://doi.org/10.3390/pharmaceutics18070885 - 20 Jul 2026

Viewed by 449

Abstract

Background: Alzheimer’s disease (AD) is the seventh leading cause of death worldwide, posing a substantial global health burden. Although galantamine (GNT) is a first-line clinical drug for AD treatment, its therapeutic efficacy is constrained by inefficient brain delivery across the blood–brain barrier [...] Read more.

Background: Alzheimer’s disease (AD) is the seventh leading cause of death worldwide, posing a substantial global health burden. Although galantamine (GNT) is a first-line clinical drug for AD treatment, its therapeutic efficacy is constrained by inefficient brain delivery across the blood–brain barrier (BBB). Nose-to-brain delivery represents a promising route to bypass the BBB. However, its efficiency remains limited by insufficient drug deposition in the anatomically restricted olfactory region. In this study, we developed a galantamine nasal spray (GNT-NS) with enhanced olfactory region deposition and evaluated its feasibility for nose-to-brain delivery in AD treatment. Methods: We optimized the formulation by systematically investigating the cascade relationship among formulation physicochemical properties, spray performance, and olfactory region deposition. Nasal deposition distribution was quantitatively evaluated using a physiologically realistic 3D-printed human nasal cavity model reconstructed from clinical magnetic resonance imaging (MRI) data. Further, the in vivo biodistribution and therapeutic efficacy of GNT-NS were evaluated in AD rats. Results: The optimized formulation P₃ achieved an olfactory region fraction of 23.85%, markedly exceeding that of the unoptimized formulation P₀. Subsequent in vivo biodistribution studies showed that P₃ produced higher brain drug exposure than both intranasally administered P₀ and the commercial oral formulation. Further pharmacodynamic studies demonstrated that GNT-NS significantly improved cognitive and behavioral deficits in AD rats, exhibiting superior therapeutic efficacy over commercially available oral galantamine tablets. Conclusions: Collectively, this study proposes a cascade regulation strategy linking formulation physicochemical properties, spray performance, and olfactory region deposition and demonstrates that optimizing nasal spray properties can enhance olfactory deposition, increase brain exposure and improve therapeutic efficacy. These findings provide a useful reference for the design of nose-to-brain delivery formulations for AD and other central nervous system diseases. Full article

(This article belongs to the Special Issue Nasal and Inhalable Drug Delivery Systems)

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18 pages, 2331 KB

Open AccessArticle

Pharmacogenomics of Rivaroxaban: Association of CYP3A4, CYP3A5, CYP2J2, ABCB1, and ABCG2 Variants with Bleeding and Thrombotic Outcomes in Real-World Clinical Practice

by Ana Marija Slišković, Vladimir Trkulja, Lana Ganoci, Tamara Božina, Vedran Pašara, Majda Vrkić Kirhmajer, Jozefina Palić, Dominik Strikić, Marino Narančić, Ivana Sopek Merkaš, Iveta Merćep, Joško Bulum and Livija Šimičević

Pharmaceutics 2026, 18(7), 884; https://doi.org/10.3390/pharmaceutics18070884 - 20 Jul 2026

Viewed by 477

Abstract

Aim: To evaluate associations between polymorphisms in CYP3A4 (*1B, *22), CYP3A5 (*3), CYP2J2 (*7, rs11572325), ABCB1 (c.1236C>T, c.2677G>T/A, c.3435C>T, rs4148738) and ABCG2 (c.421C>A) and the occurrence of bleeding [...] Read more.

Aim: To evaluate associations between polymorphisms in CYP3A4 (*1B, *22), CYP3A5 (*3), CYP2J2 (*7, rs11572325), ABCB1 (c.1236C>T, c.2677G>T/A, c.3435C>T, rs4148738) and ABCG2 (c.421C>A) and the occurrence of bleeding or occlusive events in patients receiving rivaroxaban in real-world clinical practice. Methods: A nested case-control study, divided into two substudies (bleeding and thromboembolic events), was conducted within a prospective cohort of 385 adults receiving rivaroxaban at University Hospital Centre Zagreb (September 2021–September 2024). Bleeding events were classified per ISTH criteria, and genotyping was performed using TaqMan real-time PCR. Cases and controls were balanced using entropy balancing, and associations were estimated with Bayesian logistic regression under a skeptical prior N(0, 0.355); LASSO regression was used to identify clinical and genetic predictors of outcomes. Results: In total, 71 patients (18.4%) experienced bleeding events, most frequently gastrointestinal (47.9%), while 314 patients served as controls. No pharmacogenomic variant showed a clear association with bleeding risk (raw and balanced odds ratios 0.80–1.35; 95% credible intervals crossing 1.0). LASSO regression identified age (OR 2.00 per decade), gastrointestinal comorbidity (OR 8.77), and eGFR as the dominant predictors of bleeding. Twenty-one patients experienced occlusive events (15 venous, 6 arterial); however, the low event count precluded meaningful pharmacogenomic analysis. Conclusions: Individual pharmacogenomic variants in CYP3A4, CYP3A5, CYP2J2, ABCB1, and ABCG2 together with pharmacogenetic-based phenotypes were not associated with clinically relevant bleeding in rivaroxaban-treated patients. Traditional clinical risk factors, particularly advanced age and gastrointestinal comorbidity, remain the dominant determinants of adverse outcomes. Routine pharmacogenomic testing to guide rivaroxaban dosing is not currently supported. Full article

(This article belongs to the Section Clinical Pharmaceutics)

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4 pages, 147 KB

Open AccessEditorial

Plant Extracts and Bee Products as Bioactive Compounds: From Mechanism to Delivery

by Radosław Balwierz, Ewelina Szliszka, Małgorzata Kłósek and Anna Kurek-Górecka

Pharmaceutics 2026, 18(7), 882; https://doi.org/10.3390/pharmaceutics18070882 - 20 Jul 2026

Viewed by 323

Abstract

Plant extracts and bee products have accompanied pharmacotherapy for centuries and remain among the most productive sources of pharmacologically active substances, particularly in oncology and infectious diseases [...] Full article

(This article belongs to the Special Issue Plant Extracts and Their Biomedical Applications)

20 pages, 6090 KB

Open AccessArticle

Modeling of Residence Time Distributions of Twin-Screw Extrusion Processes Considering Various Screw Types

by Vincent Kimmel, Dario Zöllig, Werner Hoheisel, Judith Winck and Markus Thommes

Pharmaceutics 2026, 18(7), 883; https://doi.org/10.3390/pharmaceutics18070883 - 18 Jul 2026

Viewed by 403

Abstract

Purpose: Residence time in pharmaceutical hot-melt extrusion is a crucial process parameter affecting the quality attributes of a dosage form such as content uniformity, bioavailability and toxicity. There is a lack of knowledge about the influence of screw element types on the [...] Read more.

Purpose: Residence time in pharmaceutical hot-melt extrusion is a crucial process parameter affecting the quality attributes of a dosage form such as content uniformity, bioavailability and toxicity. There is a lack of knowledge about the influence of screw element types on the residence time distribution, which will be addressed in this study. Methods: Different conveying and kneading elements will be characterized concerning their effect on the residence time using a co-rotating twin-screw extruder with a 28 mm screw diameter. Tracer experiments will be performed while concentration time profiles are measured via inline UV-Vis spectroscopy. Results: The residence time distribution of all screw types is primarily related to the volume flow but independent of pressure. The two-compartment model of Reitz was utilized to describe the experimental data mathematically. Screw-type-specific dimensionless parameters were derived to quantify the axial mixing performance, as well as the effect on residence time. Conclusions: The influence of different screw elements on the residence time in hot-melt extrusion processes was quantified using a dimensionless mixing volume and a dimensionless axial dispersion coefficient. The results meet the quantitative descriptions from the literature. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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20 pages, 3838 KB

Open AccessArticle

Targeting CDK4/6 in Combination with Phage-Based Anti-HER2 Vaccination Overcomes Immune Evasion and Enhances the Anticancer Response in Breast Cancer

by Junbiao Wang, Alessia Lamolinara, Daniele Tomassoni, Laura Conti, Chiara Cossu, Antonino Di Lorenzo, Mara Giangrossi, Daniela Lufrano, Varshini Vaithianathan, Fiorenza Orlando, Fabiola Olivieri, Serena Marcozzi, Daniela Beghelli, Barbara Belletti, Augusto Amici, Maurizio Falconi, Federica Cavallo, Manuela Iezzi and Cristina Marchini

Pharmaceutics 2026, 18(7), 881; https://doi.org/10.3390/pharmaceutics18070881 - 18 Jul 2026

Viewed by 975

Abstract

Background/Objectives: Cancer vaccines represent the next frontier in immunotherapy, aiming to elicit long-lasting protective anti-tumor immune responses. Human epidermal growth factor receptor 2 (HER2) is a well-established therapeutic target in breast cancer. Active immunization with HER2-displaying M13 bacteriophages can induce a therapeutic [...] Read more.

Background/Objectives: Cancer vaccines represent the next frontier in immunotherapy, aiming to elicit long-lasting protective anti-tumor immune responses. Human epidermal growth factor receptor 2 (HER2) is a well-established therapeutic target in breast cancer. Active immunization with HER2-displaying M13 bacteriophages can induce a therapeutic immune response against HER2-positive breast cancer, offering a promising alternative to trastuzumab. However, the duration of anticancer immune protection triggered by anti-HER2 phage-based vaccines is limited by tumor-immune suppressive mechanisms. Methods: In this study, two vaccination cycles with ECTM phages displaying the extracellular (EC) and transmembrane (TM) domains of human HER2 were combined with palbociclib, a CDK4/6 inhibitor, to enhance antitumor immunity in the clinically relevant Δ16HER2 transgenic preclinical model of breast cancer. Results: The proposed combination treatment resulted in a better and long-lasting control of tumor growth rate and multiplicity than either palbociclib or phage vaccination alone, correlating with a significantly stronger anti-HER2 humoral response (IgG2a isotype). Analysis of the tumor immune infiltrate revealed an increased presence of CD8⁺ T cells concomitant with a reduction in FoxP3⁺ regulatory T cells (Tregs) in tumors explanted from mice receiving the combination therapy. Conclusions: These preclinical results provide a rationale for the clinical translation of CDK4/6 inhibitors combined with anti-HER2 active immunotherapies in breast cancer, as they may yield sustained antitumor responses by reverting the immunosuppressive tumor environment. Full article

(This article belongs to the Special Issue Developing Drug Delivery Approaches for Both Phage Therapeutics and Phage-Based Vectors)

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40 pages, 26047 KB

Open AccessReview

Advances in Functional Vascular Stents for Cardiovascular Therapy with Drug Delivery and Computational Design

by Xiaotian Xu, Yan Hu, Haifang Li, Yu Wang, Jiayi Sun, Qiang Liu and Kairong Qin

Pharmaceutics 2026, 18(7), 880; https://doi.org/10.3390/pharmaceutics18070880 - 17 Jul 2026

Viewed by 602

Abstract

Vascular stents are crucial devices in the treatment of cardiovascular diseases, and their structural design and function critically affect therapeutic efficacy and patient prognosis. Conventional stents can effectively restore vascular patency by providing mechanical support to blood vessels. However, they still face significant [...] Read more.

Vascular stents are crucial devices in the treatment of cardiovascular diseases, and their structural design and function critically affect therapeutic efficacy and patient prognosis. Conventional stents can effectively restore vascular patency by providing mechanical support to blood vessels. However, they still face significant challenges including restenosis, thrombosis, and limited adaptability to complex patient-specific lesion characteristics. To address these limitations, drug delivery offers an important strategy to modulate the pathological microenvironment, enhance long-term vascular healing, and reduce systemic side effects. Meanwhile, advances in computational simulations have provided powerful tools for optimizing stent design through structural mechanics, hemodynamics, and drug release modeling. Computational approaches enable the rational design of stent architectures with improved mechanical stability, vascular compatibility, and therapeutic regulation. Consequently, the development of vascular stents is evolving toward the synergistic integration of drug delivery, structural optimization, and intelligent design. This review summarizes the latest advances in functional vascular stents, clinical applications and computational design. This work aims to provide valuable insights for the engineering of efficient, precise, and intelligent vascular stents for cardiovascular therapies. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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28 pages, 8847 KB

Open AccessArticle

Fusion Inhibition of Zika Virus Entry by a Teicoplanin Pseudoaglycone Derivative with Broad Antiviral Activity

by Zoltán Kopasz, Ilona Bereczki, Krisztina Leiner, Henrietta Papp, Eszter Boglárka Lőrincz, Levente Sipos-Szabó, Kornélia Bodó, Eszter Szabó, Mónika Madai, Brigitta Zana, Réka Erdei, Gyula Batta, Tamás Kovács-Öller, Zoltán Varga, Dávid Bajusz, Gábor Kemenesi, Anikó Borbás and Anett Kuczmog

Pharmaceutics 2026, 18(7), 879; https://doi.org/10.3390/pharmaceutics18070879 - 17 Jul 2026

Viewed by 530

Abstract

Background/Objectives: The lack of effective antiviral therapies for many viral infections highlights the need for the development of new antiviral agents. The broad antiviral effects of glycopeptide antibiotics (GPAs) and their derivatives have been previously described. In our studies, we investigated the [...] Read more.

Background/Objectives: The lack of effective antiviral therapies for many viral infections highlights the need for the development of new antiviral agents. The broad antiviral effects of glycopeptide antibiotics (GPAs) and their derivatives have been previously described. In our studies, we investigated the in vitro viral inhibitory activity of newly synthesized GPA derivatives against Zika virus (ZIKV), chikungunya virus (CHIKV), o’nyong-nyong virus (ONNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: Antiviral activity (EC50) and cytotoxicity (CC50) of the active compounds were determined using cell-based assays. The mechanism of action of the lead compound was investigated using binding and entry assays, cell-free virion pre-incubation, a virion destabilization assay, a liposome-based capsid protection assay, and molecular docking analysis. Results: Seven of the compounds were able to inhibit ZIKV and two compounds inhibited all four tested viruses. Among them, a teicoplanin pseudoaglycone derivative, compound 7, showed the strongest antiviral activity, inhibiting all four viruses at low micromolar concentrations. Mechanistic studies demonstrated that compound 7 acts during an early stage of ZIKV infection and inhibits low-pH-triggered virus–liposome fusion. Molecular docking analysis suggested potential interactions between compound 7 and the viral envelope protein that could interfere with the conformational rearrangements required for membrane fusion. Conclusions: The present findings demonstrate that hydrophobic GPA derivatives, particularly compound 7, exhibit promising broad-spectrum antiviral activity in vitro. Whether similar mechanisms contribute to the antiviral activity against other viruses remains unknown. The studied GPA derivatives are promising candidates for further pre-clinical and clinical development as broad-spectrum antivirals. Full article

(This article belongs to the Special Issue Novel Therapeutic Agents and Innovative Delivery Systems Against Infectious Diseases)

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26 pages, 8614 KB

Open AccessArticle

Natural Clinoptilolite as a Functional Mineral Component in Alginate Hybrid Microcapsules for Controlled Amoxicillin Release

by İrem Toprakçı, Ebru Kurtulbaş, Dorina Simedru, Anca Becze, Oana Cadar and Selin Şahin

Pharmaceutics 2026, 18(7), 878; https://doi.org/10.3390/pharmaceutics18070878 - 17 Jul 2026

Viewed by 453

Abstract

Background/Objectives: Natural clinoptilolite–amoxicillin hybrids (CNZ@AMOX) were incorporated into alginate microcapsules via ionic gelation to develop a hybrid mineral–polymer delivery system for the controlled release of amoxicillin. Methods: A face-centered central composite design combined with response surface methodology (FCCD-RSM) was utilized to assess the [...] Read more.

Background/Objectives: Natural clinoptilolite–amoxicillin hybrids (CNZ@AMOX) were incorporated into alginate microcapsules via ionic gelation to develop a hybrid mineral–polymer delivery system for the controlled release of amoxicillin. Methods: A face-centered central composite design combined with response surface methodology (FCCD-RSM) was utilized to assess the effects of the zeolite/sodium alginate ratio, alginate concentration, calcium chloride concentration and curing time on the encapsulation efficiency (EE), sphericity factor (SF), and roundness (Rn). Results: The EE ranged from 5.9% to 91.3%, depending on the formulation composition. Numerical optimization identified the optimal conditions as 70.962% EE, 0.05 SF and 1.00 Rn, with a desirability score of 0.873. The incorporation of natural clinoptilolite improved microcapsule structural integrity and reduced the initial burst release by modulating diffusion pathways within the hybrid matrix. The optimized CNZ@AMOX exhibited pH-dependent release behavior, with minimal drug release in simulated gastric fluid (SGF) and diffusion-controlled release in simulated intestinal fluid (SIF), which was best described by the Korsmeyer–Peppas model. Conclusions: These findings demonstrate that zeolite–alginate hybrid microcapsules represent promising inorganic–organic composite carriers for the pH-responsive and controlled delivery of AMOX. Full article

(This article belongs to the Special Issue Inorganic Nanomaterials for the Development of Drug Delivery and Biomedical Applications)

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21 pages, 693 KB

Open AccessReview

Beyond Carrier Design: Fabrication Method as the Hidden Driver of NSAID Nanomedicine Performance

by Ana-Maria Raluca Pauna, Liliana Mititelu-Tartau, Angy Abu Koush, Roxana Ionela Vasluianu, Jamal Al Ashkar, Ruxandra Teodora Stan, Viorel Radu, Marius Constantin Moraru, Cosmin Gabriel Popa, Roxana Florentina Gavril, Dragos Valentin Crauciuc, Andreea Ludusanu, Cristinel Ionel Stan and Alin Mihai Vasilescu

Pharmaceutics 2026, 18(7), 877; https://doi.org/10.3390/pharmaceutics18070877 - 17 Jul 2026

Viewed by 374

Abstract

Background/Objectives: Diclofenac (DCF) and other nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain and inflammation management; however, their clinical significance is limited by poor aqueous solubility, short biological half-life, and dose-dependent gastrointestinal, renal, and cardiovascular adverse effects. Nanocarrier-based delivery systems have been [...] Read more.

Background/Objectives: Diclofenac (DCF) and other nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain and inflammation management; however, their clinical significance is limited by poor aqueous solubility, short biological half-life, and dose-dependent gastrointestinal, renal, and cardiovascular adverse effects. Nanocarrier-based delivery systems have been extensively explored because they can enhance the apparent solubility of poorly water-soluble NSAIDs, provide controlled and sustained drug release, prolong systemic circulation, and improve drug localization at the site of action. By reducing peak plasma concentrations and off-target exposure, these systems may decrease dose-dependent gastrointestinal and systemic adverse effects while maintaining therapeutic efficacy. Most studies focus on optimizing formulation composition, while the manufacturing process is often treated as a secondary parameter. The research critically evaluates conventional and emerging fabrication methods for NSAID nanocarriers, using DCF as the principal reference compound, with emphasis on their impact on physicochemical characteristics, reproducibility, scalability, and translational potential. Methods: A structured literature search was performed in PubMed/MEDLINE, Scopus, and Web of Science (2015–2026, with emphasis on 2022–2026) for DCF and NSAID-loaded submicron delivery systems reporting quantitative formulation data and clearly defined fabrication methods, resulting in a narrative review of approximately 375–395 eligible studies, comprising 75 DCF-specific studies and approximately 300–320 studies involving other NSAIDs that were included as representative surrogate systems when DCF-specific evidence was unavailable for particular fabrication approaches. The review followed Scale for the Assessment of Narrative Review Articles (SANRA) recommendations. Studies were analyzed using a standardized seven-parameter framework including encapsulation efficiency, release profile, particle size control, polydispersity, scalability, reproducibility, and process complexity. Results: Batch-based techniques, such as thin-film hydration for chitosan-coated liposomal systems, consistently provide high encapsulation efficiency, sustained drug release, and good biocompatibility. However, these methods are often associated with batch-to-batch variability, operator dependence, and limited scalability. In contrast, continuous manufacturing approaches, including microfluidic mixing, nanostructured lipid carriers, and Quality-by-Design (QbD)–guided processes, demonstrate improved control over particle size distribution and polydispersity, enhanced reproducibility, and better scalability potential. Conclusions: Manufacturing methodology is an important determinant of DCF and NSAID nanocarrier performance alongside formulation composition. Continuous manufacturing approaches offer promising improvements in reproducibility, process control, and scalability, but current evidence remains uneven across different nanocarrier classes. Further standardized comparative studies are needed to support their broader translation into clinical applications. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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26 pages, 35951 KB

Open AccessArticle

Silver-Doped Mesoporous Calcium Phosphate for Controlled Amoxicillin Delivery and Modulation of Osteoblast-like Cell Response

by Asmaa M. El-Tohamy, Mahmoud T. Abo-elfadl and Mostafa Mabrouk

Pharmaceutics 2026, 18(7), 876; https://doi.org/10.3390/pharmaceutics18070876 - 17 Jul 2026

Viewed by 402

Abstract

Background: Calcium phosphate (CaP)-based materials are widely used for bone defect repair, but their clinical utility is often limited by insufficient antibacterial activity and a lack of controlled drug-release capability. To address this gap, the present study investigates whether silver doping can [...] Read more.

Background: Calcium phosphate (CaP)-based materials are widely used for bone defect repair, but their clinical utility is often limited by insufficient antibacterial activity and a lack of controlled drug-release capability. To address this gap, the present study investigates whether silver doping can simultaneously enhance the microstructural properties of mesoporous CaP and modulate its capacity to deliver amoxicillin in a controlled manner, thereby combining osteoconductive, antibacterial, and antibiotic-delivery functions in a single platform. Methods: Mesoporous CaP was synthesized via the polymer sacrificial method and doped with silver at two concentrations (0.5 and 1.0 wt%), both with and without amoxicillin loading, to isolate the individual and combined effects of silver and antibiotic incorporation. The resulting formulations were characterized by XRD, FTIR, SEM, and BET to establish structure–property relationships linking silver content to physicochemical and microstructural features, while their functional performance was assessed through amoxicillin release in PBS over 672 h and through biocompatibility testing on MG-63 osteosarcoma cells via MTT assay at 48, 72, and 120 h. Results: Silver incorporation was found to improve the microstructural properties of the mesoporous CaP and to progressively reduce cumulative amoxicillin release, from approximately 45% in undoped CaP to about 20% at the highest silver content, indicating that silver doping enables tunable, sustained drug release. This modulation of release was accompanied by a favorable biological profile: at 48 h, most formulations showed only moderate effects on MG-63 viability, with comparable IC₅₀ values across groups, while cytotoxicity declined and cell viability increased with longer incubation, reaching the highest proliferation at 120 h for all silver/amoxicillin-containing formulations. Conclusions: Together, these results demonstrate that silver doping does not compromise, and may enhance, the biocompatibility of mesoporous CaP even as it extends antibiotic release. This combination of tunable drug delivery, improved microstructure, and time-dependent biocompatibility positions silver-doped mesoporous CaP as a promising multifunctional platform for antibiotic delivery in bone regenerative medicine. Full article

(This article belongs to the Special Issue Biomaterials-Based Drug Delivery Systems in Regenerative Medicine)

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32 pages, 4511 KB

Open AccessArticle

Multifractal Model for Oromucosal Polymeric Film Performance

by Alexandra Barsan (Bujor), Vlad Ghizdovat, Monica Stamate Cretan, Mousa Sha’at, Carmen Anatolia Gafitanu, Ciprian Stamate, Anca Miron, Dragos-Ioan Rusu, Maricel Agop and Lacramioara Ochiuz

Pharmaceutics 2026, 18(7), 875; https://doi.org/10.3390/pharmaceutics18070875 - 17 Jul 2026

Viewed by 364

Abstract

Background: Oromucosal films are thin polymeric dosage forms designed to hydrate rapidly in the oral cavity and enable local or systemic drug delivery. Their performance depends on coupled processes including wetting, swelling, polymer relaxation, matrix softening, and structural failure. Because these phenomena [...] Read more.

Background: Oromucosal films are thin polymeric dosage forms designed to hydrate rapidly in the oral cavity and enable local or systemic drug delivery. Their performance depends on coupled processes including wetting, swelling, polymer relaxation, matrix softening, and structural failure. Because these phenomena depend strongly on the formulation composition and polymer-network organization, a mechanistic framework linking conventional characterization data to film performance is needed. This study aimed to develop a Madelung-type multifractal swelling–disintegration–release-readiness model for chitosan/hydroxypropyl methylcellulose (HPMC) films and to examine its relevance using a twelve-formulation experimental series. Methods: Twelve films based on chitosan (film-forming polysaccharide), HPMC K-4M (hydrophilic swelling polymer), glycerin (plasticizer), and starch (disintegrant) were prepared via solvent casting. The films were characterized for loss on drying, surface pH, mass and thickness uniformity, wetting time, swelling behavior, structural-disintegration onset, elongation response, rupture resistance, folding endurance, and surface roughness. The proposed model described water uptake, swelling-front motion, matrix integrity, local release-readiness activation, and hydration-induced loading as coupled fields across the film thickness. Results: Formulation markedly influenced hydration behavior, mechanical performance, structural stability, and surface morphology. Films F2 and F7 emerged as the most promising complementary unloaded matrix platforms for future active-compound incorporation and experimental release evaluation. F2 behaved as a high-swelling, mechanically stable starch-free matrix, whereas F7 combined faster wetting, starch-assisted structural destabilization, and favorable flexibility. Conclusions: This framework provides a quantitative link between empirical film characterization and formulation-level mechanistic interpretation. It translates conventional characterization parameters into descriptors related to the apparent water penetration, swelling capacity, matrix-failure tendency, mechanical suitability, and structural heterogeneity. The present results support candidate selection for future Active Pharmaceutical Ingredient-loaded studies but do not constitute validation of drug-release kinetics. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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Open AccessArticle

Potent Antimicrobial Chloroindium(III) Phthalocyanine Sensitizer Targeting Drug-Resistant Microbes: Physicochemical, Photobiological Validation and DFT Insights

by Aleksandra Pawska, Aleksey E. Kuznetsov, Marianna Szczepaniak, Daniel Ziental, Emre Güzel and Lukasz Sobotta

Pharmaceutics 2026, 18(7), 874; https://doi.org/10.3390/pharmaceutics18070874 - 17 Jul 2026

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Abstract

Background/Objectives: An evaluation of the sensitizing properties of chloroindium(III) phthalocyanine complex (InPc) bearing 4-sulfonylphenoxy groups was performed. Methods: The ability to form singlet oxygen under light exposure was assessed, and the quantum yield Φ_Δ was calculated to be 0.82 ± 0.04. Under [...] Read more.

Background/Objectives: An evaluation of the sensitizing properties of chloroindium(III) phthalocyanine complex (InPc) bearing 4-sulfonylphenoxy groups was performed. Methods: The ability to form singlet oxygen under light exposure was assessed, and the quantum yield Φ_Δ was calculated to be 0.82 ± 0.04. Under ultrasound exposure of the sensitizer (1 MHz, 3 W, 40% duty cycle), significant 1,3-diphenylisobenzofuran decomposition was observed. Results: Moreover, the macrocycle was assigned to be a moderate–high photo- and sonostable sensitizer. Density functional theory studies supported experimental results, suggesting the InPc to be a good photochemical agent. From the global reactivity parameters analysis, it can be suggested that InPc would interact easily with electron-excess species, such as various free radicals, in the solution phase, and should also be able to interact with electrophilic species. Conclusions: Studied InPc revealed high photodynamic antimicrobial activity and reached >4 log₁₀ reduction in microbial growth against methicillin-resistant Staphylococcus aureus, and 4.08 ± 0.29 log₁₀ against Candida albicans resistant to fluconazole (for dosimetry of 100 μM and 50 J/cm²). Interestingly, the photosensitizer studied was inactive against extended-spectrum β-lactamase-producing Escherichia coli. Full article

(This article belongs to the Section Biopharmaceutics)

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Pharmaceutics, Volume 18, Issue 7 (July 2026) – 138 articles

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